Journal of Medicinal Chemistry
Article
eV) m/z (%) 332 (M+, < 1), 141 (100). 3b·HCl (obtained as reported
above for 5c·HCl): yield 77%; white crystals; mp 245−247 °C
(EtOH/Et2O). IR (KBr): 3169, 1685 cm−1. 1H NMR (300 MHz,
DMSO-d6): δ 1.61 (d, J = 6.9 Hz, 3H, CH3-CH), 2.14 (s, 6H, CH3Ar),
4.00−4.18 (m, 1H, CH), 4.20−4.42 (d, 2H, CH2), 7.10 (s, 3H, Ar),
7.50−7.60 (m, 2H, Ar), 7.62−7.70 (m, 1H, Ar), 7.90−8.10 (m, 4H,
Ar), 9.52 (br s, exch D2O, 2H, NH), 9.94 (br s, exch D2O, 1H, NH) .
Anal. (C22H24N2O·HCl) C, H, N.
fraction reaches about 96%, in agreement with its hydrophobic
character with respect to Toc. The results reinforce our long-
term objective to develop a reliable pharmacophore model for
these compounds which drive the selective design of more
potent and tissue-selective Nav1.4 blockers for future
application in myotonic patients. Also, the overall profile of
6f allows us to propose this Toc analogue as a good candidate
for further studies in animal models aimed at gaining more
insight into its potential therapeutical usefulness in the
treatment of myotonias.
3-Amino-N-(2,6-dimethylphenyl)-2-methylpropanamide (5c). A
mixture of 4c (0.50 g, 2.48 mmol) and SOCl2 (3.85 mL) was stirred at
75 °C for 90 min under nitrogen atmosphere. The reaction mixture
was concentrated to dryness and used for the next step without further
purification. Then, a solution of 2,6-dimethylaniline (1.20 g, 9.84
mmol) freshly distilled in anhydrous CH2Cl2 (8 mL) was added
dropwise over 30 min under vigorous stirring at 45 °C. CH2Cl2 excess
was removed in vacuo, and the resulting brown solid was dissolved in
Et2O and washed with 2 N NaOH. The organic layer was dried (anhyd
Na2SO4), filtered, and concentrated to dryness. The crude oily residue
was purified by column chromatography on silica gel (eluting with
EtOAc/CH3OH 7:3) to provide compound 5c as a yellow oil in 88%
yield. 1H NMR (300 MHz, CDCl3): δ 1.30 (d, J = 7.1 Hz, 3H,
CH3CH), 2.21 (s, 6H, CH3 Ar), 2.45−2.52 (m, 1H, CH), 2.90−3.10
(m, 2H, CH2), 3.59 (br s, 2H, NH2), 6.67 (t, J = 7.4 Hz, 1H, Ar), 6.97
(d, J = 7.4 Hz, 2H, Ar), 9.05 (br s, 1H, NH); GC-MS (70 eV) m/z
(%) 206 (M+, 13), 121 (100). Into a solution of 5c in dry Et2O,
gaseous HCl was bubbled until saturation was reached. The organic
phase was concentrated. Purification of the crude residue solid by
recrystallization from EtOH/Et2O gave 5c·HCl as white crystals in
EXPERIMENTAL SECTION
■
Materials and Methods. Chemicals were purchased from Sigma-
Aldrich or Lancaster at the highest quality commercially available.
Solvents were of RP grade unless otherwise indicated. Yields refer to
purified products and were not optimized. The structures of the
compounds were confirmed by routine spectrometric and spectro-
scopic analyses. Melting points were recorded on a Gallenkamp
melting point apparatus in open glass capillary tubes. IR spectra were
recorded on a Perkin-Elmer Spectrum One FT spectrophotometer,
and band positions were given in reciprocal centimeters (cm−1). H
1
NMR spectra were recorded on a Varian VX Mercury spectrometer
operating at 300 MHz using CDCl3, DMSO-d6, or CD3OD as
solvents. Chemical shifts are reported in part per million (ppm)
relative to the residual nondeuterated solvent resonance: CDCl3, δ
7.26; DMSO-d6, δ 2.48; and CD3OD, δ 3.31. J values are given in Hz.
EI mass spectra were recorded on a Hewlett-Packard 6890-5973 MSD
gas chromatograph/mass spectrometer at low resolution. Elemental
analyses (C, H, N) were used to confirm the purity of all new
compounds (>95%) and were performed on a Eurovector Euro EA
3000 analyzer (results within 0.4 of the theoretical values). cLogP
and pKa values were calculated using advanced chemistry development
(ACD) software.38 Silica gel chromatographic separations were
performed by silica gel column chromatography (Kieselgel 60, 40−
63 μm, Merck, Darmstadt, Germany) as previously described.39 TLC
analyses were performed on precoated silica gel on aluminum sheets
(Kieselgel 60, F254, Merck).
1
63% yield. mp 198−199 °C. IR (KBr): 3258, 3040, 1652 cm−1. H
NMR (300 MHz, DMSO-d6): δ 1.27 (d, J = 6.6 Hz, 3H, CH3-CH),
2.12 (s, 6H, CH3Ar), 2.76−2.88 (m, 1H, CH), 2.90−3.10 (m, 2H,
CH2), 7.04 (s, 3H, Ar), 8.04 (br s, 3H, exch D2O, NH3), 9.62 (s, 1H,
NH). Anal. (C12H18N2O·HCl·H2O) C, H, N.
3-Amino-N-(2,6-dimethylphenyl)butanamide (5d). Prepared as
reported for 5c starting from 4d. The synthetic pathway provided 5d
as a yellow oil in 38% yield. 1H NMR (300 MHz, CDCl3): δ 1.25 (d, J
= 6.3 Hz, 3H, CH3-CH), 1.73 (br s, 2H, exch D2O, NH2), 2.23 (s, 6H,
CH3-Ar), 2.30−2.60 (m, 2H, CH2), 3.35−3.55 (m, 1H, CH), 7.06 (s,
3H, Ar), 9.38 (br s, 1H, NH); GC-MS (70 eV) m/z (%) 206 (M+, 12),
121 (100). 5d·HCl (obtained as reported above for 5c·HCl): yield
72%; white soft crystals; mp 169−170 °C (EtOH/Et2O). IR (KBr):
3230, 2979, 1647 cm−1. 1H NMR (300 MHz, DMSO-d6): δ 1.25 (d, J
= 6.6 Hz, 3H, CH3-CH), 2.11 (s, 6H, CH3Ar), 2.65 (dd, J = 15.1, 8.2
Hz, 1H, CHH), 2.78 (dd, J = 15.1, 5.2 Hz, 1H, CHH), 3.35−3.65 (m,
Chemistry. 1-(Bromomethyl)naphthalene (2a). The title com-
pound was prepared from 1a according to the literature procedure.30
1
The synthetic pathway provided 2a as a brown oil in 77% yield. H
NMR (300 MHz, CDCl3): δ 4.98 (s, 2H, CH2), 7.38−7.46 (m, 1H,
Ar), 7.48−7.58 (m, 2H, Ar), 7.60−7.72 (m, 1H, Ar), 7.82−7.96 (m,
2H, Ar), 8.14−8.20 (m, 1H, Ar); GC-MS (70 eV) m/z (%) 220 (M+,
9), 141 (100).
+
1H, CH), 7.04 (s, 3H, Ar), 8.20 (br s, 3H, NH3 ), 9.70 (s, 1H, NH).
Anal. (C12H18N2O·HCl·0.67H2O) C, H, N.
3-(Benzylamino)-N-(2,6-dimethylphenyl)butanamide (6e). The
title compound was prepared according to the literature procedure28
from 5d and benzyl bromide. The synthetic pathway provided 6e as a
yellow oil in 28% yield. 1H NMR (300 MHz, CDCl3) δ 1.27 (d, J = 7.1
Hz, 3H, CH3-CH), 1.56 (br s, exch D2O, 1H, NH-Bn), 2.04 (s, 6H,
CH3Ar), 2.18−2.28 (m partially overlapping dd at 2.30, 1H, CH), 2.30
(dd, J = 16.8, 3.0 Hz, 1H, CHH−CH), 2.86 (dd, J = 16.9, 10.3 Hz, 1H,
CHH-CH), 3.43 (d, J = 13.2 Hz, 1H, CHH-Bn), 3.90 (d, J = 13.4 Hz,
1H, CHH-Bn), 6.96−7.08 (m, 3H, Ar), 7.16−7.28 (m, 5H, Ar), 8.70
(br s, exch D2O, 1H, NH); GC-MS (70 eV) m/z (%) 296 (M+, 10), 91
(100). 6e·HCl (obtained as reported above for 5c·HCl): yield 79%;
white crystals; mp 236−237 °C (EtOH/Et2O). IR (KBr): 3214, 1640
cm−1. 1H NMR (300 MHz, CD3OD): δ 1.51 (d, J = 6.6 Hz, 3H, CH3-
CH), 2.22 (s, 6H, CH3Ar), 2.94 (d, J = 6.3 Hz, 2H, CH2), 4.31 (s, 2H,
CH2-Bn), 7.06−7.11 (m, 3H, Ar), 7.42−7.58 (m, 5H, Ar). Anal.
(C19H24N2O·1.50 HCl·0.50 H2O) C, H, N.
N-(2,6-Dimethylphenyl)-2-[(naphthalen-1-ylmethyl)amino]-
propanamide (3a). The title compound was prepared according to
the literature procedure30 from Toc and 2a. The synthetic pathway
provided 3a as a yellow oil in 30% yield. 1H NMR (300 MHz, DMSO-
d6): δ 1.29 (d, J = 6.9 Hz, 3H, CH3-CH), 2.14 (s, 6H, CH3Ar), 3.20−
3.50 (m, 1H, CH-CH3), 4.07 (d, J = 13.5, 1H, CHH), 4.26 (d, J = 13.5
Hz, 1H, CHH), 7.06 (s, 3H, Ar), 7.20−7.42 (m, 4H, Ar), 7.82 (d, J =
8.2 Hz, 1H, Ar), 7.86−7.96 (m, 1H, Ar), 8.16−8.24 (m, 1H, Ar), 9.35
(s, 1H, NH); GC-MS (70 eV) m/z (%) 332 (M+, < 1), 141 (100). 3a·
HCl (obtained as reported above for 5c·HCl): yield 78%; white
crystals; mp 228−229 °C (EtOH/Et2O); IR (KBr): 3170, 1684 cm−1.
1H NMR (300 MHz, CD3OD): δ 1.78 (d, J = 7.1 Hz, 3H, CH3-CH),
2.28 (s, 6H, CH3Ar), 4.35−4.50 (m, 1H, CH), 4.68 (d, J = 12.9, 1H,
CHH), 4.78 (d, J = 12.9 Hz, 1H, CHH), 7.16 (s, 3H, Ar), 7.52−7.80
(m, 4H, Ar), 7.92−8.08 (m, 2H, Ar), 8.29 (d, J = 8.0 Hz, 1H, Ar).
Anal. (C22H24N2O·HCl·0.33 H2O) C, H, N.
N-(2,6-Dimethylphenyl)-3-[(naphthalen-1-ylmethyl)amino]-
butanamide (6f). The title compound was prepared according to the
literature procedure28 from 5d and 1-(bromomethyl)naphthalene
(2a). The synthetic pathway provided 6f as a yellow oil in 23% yield.
1H NMR (300 MHz, CDCl3): δ 1.40 (d, J = 6.2 Hz, 3H, CH3-CH),
1.66 (br s, exch with D2O, 1H, NH), 2.03 (s, 6H, CH3Ar), 2.38−2.46
(dd, J = 16.2, 8 Hz, 1H, CHH−CH), 2.61−2.68 (dd, J = 16.2, 3.3 Hz,
1H, CHH−CH), 3.32−3.30 (m, 1H, CH), 4.26 (d, J = 12.6 Hz, 1H,
N-(2,6-Dimethylphenyl)-2-[(naphthalen-2-ylmethyl)amino]-
propanamide (3b). The title compound was prepared according to
the literature procedure30 from Toc and 2b. The synthetic pathway
provided 3b as a yellow oil in 30% yield. 1H NMR (300 MHz, DMSO-
d6) δ 1.28 (d, J = 6.9 Hz, 3H, CH3-CH), 2.12 (s, 6H, CH3Ar), 3.25−
3.60 (m, 1H, CH), 3.79 (d, J = 13.5 Hz, 1H, CHH), 3.96 (d, J = 13.5
Hz, 1H, CHH), 7.05 (s, 3H, Ar), 7.40−7.50 (m, 2H Ar), 7.50−7.58
(m, 1H, Ar), 7.78−7.90 (m, 4H, Ar), 9.37 (s, 1H, NH). GC-MS (70
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dx.doi.org/10.1021/jm401864b | J. Med. Chem. 2014, 57, 2589−2600